The polycystic ovary syndrome (PCOS) affects approximately 6-10% of women of reproductive age and is characterized by chronic anovulation and hyperandrogenism. Most women with PCOS are also characterized by insulin resistance, and our long-term goal is to elucidate the relationship between insulin resistance and PCOS. Some actions of insulin may be effected by putative inositolphosphoglycan (IPG) mediators of insulin action, and evidence suggests that a deficiency in a specific D-chiro-inositol-containing IPG (DCI-IPG) may contribute to insulin resistance in women with PCOS. We successfully refined and validated a bioactivity assay for DCI-IPG, and assessed DCI metabolism and insulin sensitivity in both women with PCOS and a group of normal control women. We found that women with PCOS, when compared to normal women, had a 1) greater than 5-fold increase in the renal clearance of DCI, 2) 50% reduction in the circulating concentration of DCI, and 3) decreased insulin-stimulated release of DCI-IPG during an OGTT. Moreover, insulin sensitivity (as determined by FSIVGTT) correlated inversely with renal clearance of DCI in all women. These findings are consistent with abnormal handling of DCI in PCOS that results in impaired release of the DCI-IPG mediator and, consequently, insulin resistance. We propose to test the hypothesis that DCI metabolism itself is regulated by insulin in PCOS, such that hyperinsulinemia increases renal clearance of DCI, resulting in deficiencies in DCI and DCI-IPG, and that this is specific for PCOS and does not occur in normal women. If this proves correct, it would suggest that an initial "insult" producing insulin resistance/hyperinsulinemia in a woman with PCOS would be amplified by a "vicious cycle" in which renal clearance of DCI is increased, yielding a deficiency in the DCI-IPG mediator, which in turn further decreases insulin sensitivity. Such a mechanism could account for the observation that insulin resistance in women with PCOS is substantially greater than that of age- and BMI-matched healthy women.